Numerous studies have demonstrated that low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Atherosclerosis 1996; 121: 1-12). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids, while other classes of lipoproteins include low density lipoprotein (LDL) and very low density lipoprotein (VLDL). High LDL cholesterol and triglycerides are positively correlated, while high levels of HDL cholesterol are negatively correlated with the risk for developing cardiovascular diseases like atherosclerosis, coronary heart disease, peripheral vascular disease, stroke and the like.
Cholesteryl ester transfer protein (CETP) is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Lipid Res 1993; 34: 1255-74). Among the various factors controlling plasma levels of these disease dependent principles, CETP activity affects all three. The role of this plasma glycoprotein is to transfer cholesteryl ester and triglyceride between lipoprotein particles including HDL, LDL and VLDL. The net result of CETP activity is a lowering of HDL cholesterol and increase of LDL cholesterol, the effect of which is proatherogenic. Thus, inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (Medicinal Res Revs 1993; 13: 139-59; Pharma. Therap 1995; 67: 443-447). 4-Carboxyamino-2-substituted 1,2,3,4-tetrahydroquinolines have been disclosed in U.S. Pat. No. 6,197,786. WO 0018721 discloses substituted polycyclic aryl and heteroalyl tertiary-heteroalkylamines with cholesteryl ester transfer protein inhibiting activity, compositions and method for treating atherosclerosis and other coronary artery diseases. WO 2005033082 discloses CETP inhibitors and metabolites. US 20050059810 disclose a novel CETP activity inhibitor dibenzylamine compound and its medicinal use. WO 2006013048 describes indole, indazole or indoline derivatives as CETP inhibitors. US2006/122224 discloses quinoline and quinoxaline compounds as CETP inhibitors. WO 2006/072362 reported the use of tetrahydroquinoline derivatives as CETP inhibitors.
Very few compounds which are modulators of CETP are there in the market and looking at the tremendous increase in life style related diseases like atherosclerosis, coronary heart attack etc. and the role CETP plays in their pathophysiological manifestation, there exists a need for providing further compounds which are modulators of the CETP protein. Surprisingly, in preliminary experiments carried out it has been found that the compounds of general formula (1), such as herein described, are modulators of HDL. Such compounds preferably, may also be suitable as inhibitors of CETP.